Differential loss of chromosome 11q in familial and sporadic parasympathetic paragangliomas detected by comparative genomic hybridization

Parasympathetic paragangliomas (PGLs) represent neuroendocrine tumors arising from chief cells in branchiomeric and intravagal paraganglia, which share several histological features with their sympathetic counterpart sympathoadrenal paragangliomas. In recent years, genetic analyses of the familial form of PGL have attracted considerable interest. However, the majority of paragangliomas occurs sporadically and it remains to be determined whether the pathogenesis of sporadic paraganglioma resembles that of the familial form. Furthermore, data on comparative genetic aberrations are scarce. To provide fundamental cytogenetic data on sporadic and hereditary PGLs, we performed comparative genomic hybridization using directly fluorochrome-conjugated DNA extracted from 12 frozen and 4 paraffin-embedded tumors. The comparative genomic hybridization data were extended by loss of heterozygosity analysis of chromosome 11q. DNA copy number changes were found in 10 (63%) of 16 tumors. The most frequent chromosomal imbalance involved loss of chromosome 11. Six of seven familial tumors and two of nine sporadic tumors showed loss of 11q (86% versus 22%, P = 0.012). Deletions of 11p and 5p were found in two of nine sporadic tumors. We conclude that overall DNA copy number changes are infrequent in PGLs compared to sympathetic paragangliomas and that loss of chromosome 11 may be an important event in their tumorigenesis, particularly in familial paragangliomas

Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas

Despite several loss of heterozygosity studies, a comprehensive genomic survey of pheochromocytomas is still lacking. To identify DNA copy number changes which might be important in tumor development and progression and which may have diagnostic utility, we evaluated genetic aberrations in 29 sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign tumors and 10 malignant lesions). Comparative genomic hybridization was performed using directly fluorochrome-conjugated DNA extracted from frozen (16) and paraffin-embedded (13) tumor tissues. The most frequently observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q (34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%) and 17q (31%). No amplification was identified and no difference between adrenal and extra-adrenal tumors was detected. Progression to malignant tumors was strongly associated with deletions of chromosome 6q (60% versus 21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%). Fluorescence in situ hybridization confirmed the comparative genomic hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy in some tumors. Our results suggest that the development of pheochromocytomas is associated with specific genomic aberrations, such as losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor suppressor genes on chromosomes 1p and 3q may be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma:The EORTC 1608 STEAM trial

Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. Methods: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.Results: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. Conclusions: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.</p

Below-elbow cast sufficient for treatment of minimally displaced metaphyseal both-bone fractures of the distal forearm in children: long-term results of a randomized controlled multicenter trial

Background and purpose — We have previously shown that children with minimally displaced metaphyseal both-bone forearm fractures, who were treated with a below-elbow cast (BEC) instead of an above-elbow cast (AEC), experienced more comfort, less interference in daily activities, and similar functional outcomes at 7 months’ follow-up (FU). This study evaluates outcomes at 7 years’ follow-up. Patients and methods — A secondary analysis was performed of the 7 years’ follow-up data from our RCT. Primary outcome was loss of forearm rotation compared with the contralateral forearm. Secondary outcomes were patient-reported outcome measures (PROMs) consisting of the ABILHAND-kids and the DASH questionnaire, grip strength, radiological assessment, and cosmetic appearance. Results — The mean length of FU was 7.3 years (5.9–8.7). Of the initial 66 children who were included in the RCT, 51 children were evaluated at long-term FU. Loss of forearm rotation and secondary outcomes were similar in the 2 treatment groups. Interpretation — We suggest that children with minimally displaced metaphyseal both-bone forearm fractures should be treated with a below-elbow cast

Effectiveness and cost-effectiveness of transmural collaborative care with consultation letter (TCCCL) and duloxetine for major depressive disorder (MDD) and (sub)chronic pain in collaboration with primary care: design of a randomized placebo-controlled multi-Centre trial: TCC:PAINDIP

__Abstract__ Background: The comorbidity of pain and depression is associated with high disease burden for patients in terms of disability, wellbeing, and use of medical care. Patients with major and minor depression often present themselves with pain to a general practitioner and recognition of depression in such cases is low, but evolving. Also, physical symptoms, including pain, in major depressive disorder, predict a poorer response to treatment. A multi-faceted, patient-tailored treatment programme, like collaborative care, is promising. However, treatment of chronic pain conditions in depressive patients has, so far, received limited attention in research. Cost effectiveness of an integrated approach of pain in depressed patients has not been studied. This article describes the aims and design of a study to evaluate effects and costs of collaborative care with the antidepressant duloxetine for patients with pain symptoms and a depressive disorder, compared to collaborative care with placebo and compared to duloxetine alone

Heritability of cortisol production and metabolism throughout adolescence: a twin study

CONTEXT: Inter-individual differences in cortisol production and metabolism emerge with age and may be explained by genetic factors. OBJECTIVE: To estimate the relative contributions of genetic and environmental factors to inter-individual differences in cortisol production and metabolism throughout adolescence. DESIGN: Prospective follow-up study of twins. SETTING: Nationwide register. PARTICIPANTS: 218 mono- and dizygotic twins (N = 109 pairs) born between 1995 amd 1996, recruited from the Netherlands Twin Register. Cortisol metabolites were determined in 213, 169, and 160 urine samples at the ages of 9, 12, and 17, respectively. MAIN OUTCOME MEASURES: The total contribution of genetic factors (broad-sense heritability) and shared and unshared environmental influences to inter-individual differences in cortisol production and activities of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenases and cytochrome P450 3A4. RESULTS: For cortisol production rate at the ages of 9, 12, and 17, broad-sense heritability was estimated as 42%, 30%, and 0%, respectively, and the remainder of the variance was explained by unshared environmental factors. For cortisol metabolism indices, the following heritability was observed: for the A-ring reductases (5α-and 5β-reductases), broad-sense heritability increased with age (to >50%), while for the other indices (renal 11β-HSD2, global 11β-HSD, and CYP3A4), the contribution of genetic factors was highest (68%, 18%, and 67%, respectively) at age 12. CONCLUSIONS: The contribution of genetic factors to inter-individual differences in cortisol production decreased between 12 and 17y, indicative of a predominant role of individual circumstances. For cortisol metabolism, distinct patterns of genetic and environmental influences were observed, with heritability that either increased with age or peaked at age 12y